Cerebral venous thrombosis associated with extracranial tumours: a clinical series

Transcription

1 Progress in Neuroscience Vol.1, N. 1-4, 2013 Original article Cerebral venous thrombosis associated with extracranial tumours: a clinical series S. IURLARO, A. SILVANI*, M. MAURI**, G. TRUCI***, S. BERETTA****, A. ZILIOLI, M. GUIDOTTI**, A. SALMAGGI**, C. FERRARESE****, G. COMI***, M. RIVA Department of Neurology, Azienda Ospedaliera, Lodi, Italy * Department of Neuro-oncology, C. Besta Neurological Institute, Milan, Italy ** Department of Neurology, Valduce Hospital, Como, Italy *** Department of Neurology, S. Raffaele Hospital, University Vita Salute, Milan, Italy **** Department of Neurology, S. Gerardo Hospital, University of Milan-Bicocca, Monza, Italy SUMMARY: AIM. Cerebral Venous Thrombosis (CVT) may occur at the clinical onset of malignancies or complicate their course, even in a quiescent phase, and the literature contains several case reports linking the two diseases. However, thus far only one article has been written with the specific objective of reporting the characteristics of CVT in cancer patients. We therefore set out to analyse the clinical characteristics of CVT associated with extracranial tumours. MATERIALS AND METHOD. We identified 9 cases of CVT in adults (> 15 years) affected by extracranial tumours seen in 6 hospitals from January 2004 to December RESULTS. The median age of patients was 40 years (range years). Eight out of the 9 patients were female. Associated tumours were: lymphoma (4 patients); breast (2 patients), rhinopharyngeal (1 patient) and gastric (1 patient) s. One patient presented concurrent kidney tumour and melanoma. In the majority of patients (7/9), CVT onset was metachronous, while it was synchronous in the remainder. In all cases, diagnosis of CVT was based on cerebral angiography, CT venography or brain MRI/MR venography. Multiple es were affected in 7 out of the 9 patients, and parenchymal lesions were also detected in 7 patients. In the acute phase, all patients were anticoagulated with unfractionated heparin (2 cases) or subcutaneous low-molecularweight heparin (7 patients) at therapeutic doses. None went on to develop further haemorrhagic complications. At discharge, the patients presented a complete recovery in 4 of the 9 cases, mild sequelae in 4/9, and moderate sequelae in 1/9. At 6-month follow-up, 2 patients had died due to tumour progression, one patient presented arterial stroke, and one patient partial seizures. CONCLUSIONS. In our cases, all female, the active phase of tumour and malignant haemolymphoproliferative diseases were associated with CVT. The anticoagulant therapy administered did not lead to an increased risk of haemorrhagic complications, and the patients long-term prognoses were conditioned by the tumours themselves. KEY WORDS: Cerebral venous thrombosis, Extracranial tumour, Outcome, Therapy. INTRODUCTION Cerebral venous thrombosis may occur at the clinical onset of malignancies or complicate their course, even in a quiescent phase (11,19). Raizer identified twenty cases of CVT (a prevalence of 0.3%) in a population Correspondence: Dr. Maurizio Riva, Dipartimento di Neurologia, Azienda Ospedaliera della Provincia di Lodi, viale Savoia 10, Lodi (LO), Italy, ph. +39-(0) , fax +39-(0) , maurizio.riva@ao.lodi.it Progress in Neuroscience 2013; 1 (1-4): ISSN: Article received: 19 February doi: /PiN.2013.Riva.91 Copyright 2013 by new Magazine edizioni s.r.l., via dei Mille 69, Trento, Italy. All rights reserved

2 Cerebral venous thrombosis associated with extracranial tumours: a clinical series S. Iurlaro LIST OF ACRONYMS AND ABBREVIATIONS: AE = Antiepileptic Therapy; AIRTUM = Associazione Italiana dei Registri TUMori; CT = Computed Tomography; CVT = Cerebral Venous Thrombosis; EFNS = European Federation of Neurological Societies; HM = Haematological Malignancies; ISCVT = International Study on Cerebral Vein and Dural Sinus Thrombosis; KPS = Karnofsky Performance Status; LMWH = Low-Molecular-Weight Heparin; MRI = Magnetic Resonance Imaging; mrs = Modified Rankin Scale; MSKCC = Memorial Sloan-Kettering Cancer Center; UFH = UnFractionated Heparin: SD = Standard Deviation: ST = Solid Tumours; SEER = Surveillance, Epidemiology and End Results. of 7,029 cancer patients evaluated over about five years (17). In a recent international multicenter study, which included 624 patients with symptomatic CVT, cancer represented a risk factor in 7.4% of these cases (8). The literature contains several case reports linking cerebral venous thrombosis with malignancies (12). However, thus far only one article has been written with the specific objective of reporting the characteristics of cerebral thrombosis in cancer patients (17). This collated data from the neurology database at the Memorial Sloan-Kettering Cancer Center on twenty cancer patients diagnosed with CVT between January 1994 and April Unlike our series, this sample also includes patients with intracranial neoplasms. Conversely, the other series documented in literature gathered data pertaining to cases of cerebral venous thrombosis in the general population (8), making it impossible to extrapolate the clinical and demographic features of CVT in the selected category of cancer patients. AIM. Our objective was to analyse the clinical characteristics of CVT associated with extracranial tumours. MATERIAL AND METHODS We identified 9 cases of CVT in adults (> 15 years) affected by extracranial tumours seen in 6 local care provision institutions (6 from general hospitals, 2 from university hospitals and 1 from a research hospital) from January 2004 to December 2009 (Table 1). For inclusion, the diagnosis of CVT had to be confirmed by conventional angiography, CT venography, or brain MRI combined with MR venography. The following information pertaining to these cases was reviewed in detail: demographic features; time span between symptom onset and hospital admission; evolution of symptoms and signs from onset to final diagnosis and follow-up; modified Rankin Scale score and Karnofsky performance status on admission and at discharge; imaging methods used; location of the thrombus; number, location, and size of any parenchymal lesion; associated tumour and disease staging; any other potential risk factors for cerebrovascular disease; type of CVT treatment; and followup at 6 months. In the interests of clarity, the data collected is reported as percentages in both the text and the tables. RESULTS The median age was 40 years (range: years), and 8 of the nine patients were female. In all cases, basal (pre-cvt) mrs was 0 and %. The diagnosis of CVT was established by MRI/MR venography in 8 patients and intra-arterial angiography in one. The onset of CVT was acute in 4 patients, subacute in 4 patients, and in one case it was an accidental finding (imaging for the diagnosis of an arterial stroke). The clinical manifestations were: focal deficits (7/9), headache (6/9), seizures (4/9) and consciousness disorders (3/9). Isolated or associated headache was the most frequent clinical symptom at CVT onset (6 patients). The clinical features of all patients are shown in Table 2. Associated tumours (all confirmed by histology) were: lymphoma (4 patients); and breast (2 patients), rhinopharyngeal (1 patient) and gastric (1 patient) s. One patient presented both a kidney tumour and a melanoma concurrently. In most of the patients (7/9), CVT onset was metachronous, while it was synchronous in the remainder. Malignancies were active in most cases (8/9). Associated risk factors detected were: chemotherapy in 4 patients, hyperhomocysteinaemia in 2; oral contraceptive in 2; factor V Leiden mutation in one and steroids in one (5,16). In two patients malignancies represented the only risk factor for CVT. Multiple es were affected and MRI showed parenchymal lesions in 7 patients (only venous infarctions in 3 patients and satellite haemorrhages in 4). Parenchymal lesions were multiple in 3 patients. The es involved are detailed in Table 3. In the acute phase, all the patients were anticoagula

3 Progress in Neuroscience Vol.1, N. 1-4, 2013 Demographic and clinical data of our patients Patients Sex Age Tumours Other risk factors Clinical onset of CVT Clinical manifestations Involved es/veins Parenchymal lesions Therapy Outcome at discharge Outcome at 6 months ET F 75 Breast Chemotherapy Acute Focal deficits, disorder of consciousness Straight, deep venous system Yes LMWH mrs 2 KPS 60 Lost at follow up LF F 59 Gastric Steroids Chance discovery None Lateral, jugular vein No LMWH Ischaemic stroke: mrs 3 KPS 50 BS F 32 Lymphoma None Acute Focal deficits, seizures, lateral Yes LMWH KPS 90 mrs 6 SC F 29 Lymphoma Chemotherapy Acute focal deficits, seizures Yes LMWH RV F 40 Breast Oral contraceptive, hyperhomocysteinaemia FP F 24 Lymphoma Chemotherapy, factor V Leiden mutation Subacute Acute focal deficits focal deficits, seizures Straight, deep venous system, lateral Yes Unfractionated heparin mrs 2 KPS 70 Yes LMWH mrs 1 mrs 1 BE F 31 Lymphoma Chemotherapy, oral contraceptive, MTHFR A1298C mutation Subacute focal deficits, seizures, disorder of consciousness, lateral Yes Unfractionated heparin Seizures PAM F 59 Kidney tumor and melanoma Hyperhomocysteinaemia Subacute focal deficits, straight, lateral Yes LMWH mrs 1 mrs1 GC M 61 Rhinopharyngeal None Subacute disorder of consciousness, ocular movement deficits Cavernous No LMWH mrs 3 KPS 50 mrs 6 Table 1. Demographic and clinical data of our patients. Clinical manifestations Clinical manifestations Our patients (%) Raizer s study Masuhr s Review Occluded cerebral es and/or veins Headache 6 (67%) 40% 75-95% Focal deficits 7 (78%) 20% 40-60% Early seizures 4 (44%) 30% 35-50% Consciousness disorders 3 (33%) 15% 15-19% Table 2. Clinical manifestations. Occluded es/veins No. of Cases % 5 56 Lateral 5 56 Straight 3 33 Deep venous system 2 22 Jugular veins 1 11 Cavernous 1 11 Table 3. Occluded cerebral es and/or veins

4 Cerebral venous thrombosis associated with extracranial tumours: a clinical series S. Iurlaro Outcome at discharge Our patients ISCVT* No. of Cases % % Death Modified Rankin Scale mrs mrs mrs mrs mrs Karnofsky performance status Table 4. Outcome. Legend: * = International Study on Cerebral Vein and Dural Sinus Thrombosis. Data pertaining to all the cases (8). ted with unfractionated heparin (2 cases) or subcutaneous low-molecular-weight heparin (7 patients) at therapeutic doses. No patient went on to develop further haemorrhagic complications. Additional treatments included analgesic drugs (3 patients) and antibiotic therapy (2 patients). Only half (2/4) of our patients with early seizures were prescribed prophylactic antiepileptic therapy. Detailed information on outcome at discharge was available for all patients (Table 4). This showed a complete recovery () in 4 patients, mild sequelae (mrs 1-2) in 4 and moderate sequelae (mrs 3) in one. Median KPS was 100% and average KPS 86% (SD 20.1, range: %). At 6-month follow-up, 2 patients had died due to tumour progression, one patient had suffered an arterial stroke, and one patient had developed partial seizures. We divided the patients into two subgroups: those with haematological malignancies (HM, 4 patients) and those with solid tumours (ST, 5 patients), as shown in Table 5. Although the sample was small, some differences between the two sub-groups did emerge. In particular, the patients with HM were younger and developed focal deficits and seizures more frequently than the ST subgroup. The patients with ST had a more frequent involvement of the deep cerebral venous system and a worse prognosis in the short term. DISCUSSION Analysis of the two subgroups HM (4 Patients) ST (5 Patients) Median age 30 years 59 years Female 4 (100%) 4 (80%) Clinical manifestation - Headache 3 (75%) 3 (60%) - Focal deficits 4 (100%) 3 (60%) - Seizures 4 (100%) 0 (0%) - Consciousness disorders 1 (25%) 4 (40%) Thrombosis of cerebral deep venous system Outcome at discharge 0 (0%) 3 (60%) - Median 2 - Median 70 Table 5. Analysis of the two subgroups: Haematological Malignancies (HM) and Solid Tumours (ST). Ferro s multicenter study reports data on CVT in the general population, and the data regarding their subgroup of cancer patients cannot therefore be extrapolated (8). In the ISCVT, the median age was 37 years (range: 16-89), and 74.5% of the patients were female. These demographic features, pertaining to the general population, are similar to those describing our series of cancer patients and are those recently reported in the literature (2,8,14). In Raizer s retrospective study at the MSKCC, New York (17), the median age of patients was 44.5 years (range: 10-71) with a prevalence of male gender (80% of the patients). It is nevertheless important to note that Raizer s study also included paediatric patients, who present a different gender prevalence for CVT. In our series, 4 patients exhibited haematological malignancies and 5 solid tumours. This is similar to Raizer s sample: he found 9 patients (44.5%) with

5 Progress in Neuroscience Vol.1, N. 1-4, 2013 HM and 11 patients (55.5%) with ST (17). According to the AIRTUM (Italian Tumour Registry) Work Group (1), haematologic malignancies make up 9.5% of all the extracranial tumours registered in Italy. Similar data are reported for the US on the SEER website ( seer.cancer.gov/). Judging by the higher prevalence of haematological tumours in both our series and that documented by Raizer with respect to the general cancer population, it may be possible to postulate an increased risk of CVT and haemolymphoproliferative disease (15). Recent reviews of the literature report a frequency of focal signs of 40-60%, mainly related to the presence of parenchymal lesions (14). In Ferro s multicenter prospective study, the greatest cumulative reported focal deficit was 65% (8), whereas in our patients the incidence of neurological focal signs was 78%. This difference may be due to a greater presence of parenchymal lesions in our series (78%) than in similar data reported in the general population (63% in the ISCVT). In contrast, Raizer reported a frequency of focal deficits of 20% (17), significantly lower than both our series and literature data. Although in our patients headache was not the most frequent clinical manifestation in the course of the disease, as it is in the literature (5,14), it was the principal symptom of CVT onset (6/9 cases). As there is a strong correlation between early CVT diagnosis and favourable outcome (quoad vitam and quoad valetudinem) (8,9), headache should not be underestimated in cancer patients, even when brain CT scan is normal (as is the case in 30% of confirmed CVTs in the general population) (2). Where there is cause for clinical doubt, brain MRI/MR venography should be performed. In the literature, the incidence of early seizures is 35-50% of the cases (14). Indeed, four patients (44%) in our series presented seizures, as did 30% of Raizer s patients (17). In our cases, the seizures were associated with focal deficits and parenchymal lesions, seen by neuroimaging (cerebral CT or MRI), and thrombosis of superior sagittal, as reported in the literature (7). In the Portuguese series (9), late seizures occurred within the first year, and a visible haemorrhagic lesion in the acute imaging was the strongest predictor of post-acute seizures. In all series together, however, late seizures were more common in patients with early symptomatic seizures than in those patients with none (6,9). In our series, one patient developed late partial seizures at 6-month follow-up. She had also presented early seizures over the course of her CVT, and the brain CT scan in the Emergency Room showed venous infarction with haemorrhagic lesions. Although we agree with the EFNS guideline suggestion that AE represents a reasonable therapeutic option - for up to one year - in patients with early seizures and haemorrhagic lesions on admission brain scan (6), the patient in question was not given any prophylactic antiepileptic therapy. Epilepsy in cancer patients is a major concern, mainly as regards indications to treatment, as well as the toxicity and pharmacokinetic and pharmacodynamic interactions of coadministered drugs (18,20). The management of cerebral venous thrombosis associated with cancer is extrapolated from the treatment of CVT from all causes (11,19). Anticoagulants with body-weight-adjusted subcutaneous low-molecularweight heparin or unfractionated heparin are widely used as first-line therapy (2,6,8). Anticoagulant therapy should also be used in patients with intraparenchymal haemorrhage (6). In our series, the anticoagulant therapy did not affect the cytotoxic/cytostatic treatment, and was not associated with any further haemorrhagic complications. Hence, although ours is a small series of patients, and in spite of all the problems of potential haematological toxicity and interference with other drugs, our experience confirms the usefulness of anticoagulant therapy in the subgroup of patients with CVT associated with extracranial tumours (13). A subgroup analysis of the ISCVT sample shows how malignancies did not represent a risk factor for mortality 30 days after CVT (4). Our data yield similar results, as in our patients cancer did not influence the short-term outcome of CVT if diagnosed and treated early. It is impossible to draw a correlation between anticoagulant therapy and outcome at discharge in Raizer s study (17). In fact, there were multiple types of treatment (no therapy, anticoagulant therapy, freshfrozen plasma, cranial radiotherapy in metastatic infiltration) and the outcome of each therapy was not reported. In ISCVT, malignancies represented a relevant risk factor for disability and death at long-term follow-up (hazard ratio for mortality and dependency 2.90, 95% CI ) (4). This result may be explained by the tumour progression, as confirmed in our series (two patients died within the first year as a consequence of their cancer). In Raizer s study too, in most cases the long-term negative outcome was due to malignancies and it was not a direct consequence of CVT (17). Analysis of our data showed a significantly lower

6 Cerebral venous thrombosis associated with extracranial tumours: a clinical series S. Iurlaro median age in patients with HM (30 years) than in those with ST (59 years). This is also in line with Raizer s findings (17). However, we also observed a poor outcome at discharge (evaluated by mrs and KPS) in patients with solid tumours, and a highly significant difference in seizure frequency between the two subgroups (100% in HM; 0% in ST). The difference in short-term outcome may be explained by the fact that consciousness disorders and thrombosis of the deep venous system were more frequent in the ST group, whose median age was > 37 years. These are known as risk factors for poor prognosis of CVT in the general population (3,10). CONCLUSION In our cases, all female, the active tumour phase and malignant haemolymphoproliferative diseases were associated with CVT. Anticoagulant therapy did not increase the risk of haemorrhagic complications, and the patients general long-term prognosis was only influenced by the cancer. REFERENCES 1. Associazione Italiana dei Registri TUMori (AIRTUM) Working Group. [Italian cancer figures, report 2010: Cancer prevalence in Italy. Patients living with cancer, long-term survivors and cured patients.] Epidemiol Prev 2010; 34 (5-6 Suppl 2): Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. Lancet Neurol 2007; 6 (2): Breteau G, Mounier-Vehier F, Godefroy O, Gauvrit JY, Mackowiak-Cordoliani MA, Girot M, Bertheloot D, Hénon H, Lucas C, Leclerc X, Fourrier F, Pruvo JP, Leys D. Cerebral venous thrombosis 3-year clinical outcome in 55 consecutive patients. J Neurol 2003; 250 (1): Canhão P, Ferro JM, Lindgren AG, Bousser MG, Stam J, Barinagarrementeria F. Causes and predictors of death in cerebral venous thrombosis. Stroke 2005; 36 (8): Canhão P, Cortesao A, Cabral M, Ferro JM, Stam J, Bousser MG et al. Are steroids useful to treat cerebral venous thrombosis? Stroke 2008; 39 (1): Einhäupl K, Stam J, Bousser MG, De Bruijn SF, Ferro JM, Martinelli I et al. EFNS guideline on the treatment of cerebral venous and thrombosis in adult patients. Eur J Neurol 2010; 17 (10): Ferro JM, Canhão P, Bousser MG, Stam J, Barinagarrementeria F. Early seizures in cerebral vein and dural thrombosis: risk factors and role of antiepileptics. Stroke 2008; 39 (4): Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral vein and dural thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35 (3): Ferro JM, Correia M, Pontes C, Baptista MV, Pita F; Cerebral Venous Thrombosis Portuguese Collaborative Study Group (Venoport). Cerebral vein and dural thrombosis in Portugal: Cerebrovasc Dis 2001; 11 (3): Gosk-Bierska I, Wysokinski W, Brown RD, Jr., Karnicki K, Grill D, Wiste H, Wysokinska E, McBane RD 2nd. Cerebral venous thrombosis: Incidence of venous thrombosis recurrence and survival. Neurology 2006; 67 (5): Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine 1985; 64 (1): Haan J, Caekebeke JF, van der Meer FJ, Wintzen AR. Cerebral venous thrombosis as presenting sign of myeloproliferative disorders. J Neurol Neurosurg Psychiatry 1988; 51 (9): Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25 (34): Masuhr F, Mehraein S, Einhaupl K. Cerebral venous and thrombosis. J Neurol 2004; 251 (1): Meininger V, James JM, Rio B, Zittoun R. Dural venous thrombosis in blood diseases. Rev Neurol 1985; 141 (3): Plotkin SR, Wen PY. Neurologic complications of cancer therapy. Neurol Clin 2003; 21 (1): Raizer JJ, DeAngelis LM. Cerebral thrombosis diagnosed by MRI and MR venography in cancer patients. Neurology 2000; 54 (6): Riva M. Brain tumoral epilepsy: a review. Neurol Sci 2005; 26 (Suppl 1): Rogers LR. Management of stroke in cancer. Curr Oncol Rep 2008; 10 (1): Rossetti AO, Stupp R. Epilepsy in brain tumor patients. Curr Opin Neurol 2010; 23 (6): DISCLOSURE. The Authors declare no conflicts of interest